Allogeneic stem cell transplantation has broad implications as a therapeutic strategy for treating diseases such as cancer, autoimmune disease, and genetic disorders as well as for induction of specific immune tolerance for transplanted solid organs. A number of previous experimental studies have shown that depletion of primitive stem cells is often required in the host before long-term engraftment (chimerism) from donor stem cells is achieved. In myeloablative protocols, this is accomplished with high doses of irradiation or pharmacological agents such as busulfan. Many non-myeloablative protocols currently being evaluated depend, at least in part, on mature T cells present in the donor graft to provide this function. Engraftment achieved in this manner, however, is often associated with graft-versus-host disease (GVHD). Our goal in this Phase I proposal is to demonstrate proof of concept that a monoclonal antibody specifically directed against hematopoietic stem cells of the recipient can be substituted for toxic agents such as busulfan, thus eliminating the requirement for donor T cells in non-myeloablative transplant protocols and reducing the likelihood of GVHD. Phase II will be proof of concept in a relevant primate model of allogeneic stem cell transplantation.